REGULATION OF B CELL MEMORY

记忆B细胞通过淋巴组织中的一条特殊途径分化 生发中心(GC)，与生发中心不同且独立于生发中心 抗体的形成，包括体细胞突变和选择 对抗原有高亲和力的细胞。GC/记忆的调节 途径，这代表了最重要的适应性免疫机制， 人们对此知之甚少。这项提案将检验关于以下三个新想法 这项规定。一、推测B细胞的GC/记忆通路 分化是由专门的辅助T细胞(TH)亚群驱动的。 这些TH将通过细胞分选和细胞克隆来分离，它们的 收养后的特性和作用机制将在体内进行研究 半抗原免疫的重组B细胞SCID小鼠体内的转移 载流子共轭。胚胎生发中心(GC)的发育 脾将通过免疫组织化学技术进行监测， 将测定半抗原特异性血清抗体的亲和力。这个 GcB细胞的体细胞超突变活性将通过 编码H链的重排VDJ片段的序列分析 半抗原特异性抗体。第二，建议GC/Memory响应 可以用抗原(Ag)与抗体的复合物选择性地刺激 (AB)。这一假设将使用已知的定义明确的抗体进行检验 日本血吸虫抗原/抗体复合体的同工型、亲和力及其作用机制 结合特定TH子集和克隆提供的帮助， 被研究。第三，提出了确定记忆B是否 骨髓中的细胞，这似乎是 记忆抗体反应与骨髓环境是否起作用 对记忆力的额外分子和功能的成熟 抗体库。拟议的研究将阐明重要的 免疫记忆的机制，提供了操纵 适应性免疫反应，并提出新的疫苗接种策略。

Memory B cells differentiate via a specialized pathway in the lymphoid germinal centers (GC) which is different from, and independent of the antibody formation and which includes somatic mutation and selections of cells with high affinity for the antigen. The regulation of the GC/memory pathway, which represents the most important adaptive immune mechanism, is poorly understood. This proposal will test three novel ideas about this regulation. One, it is postulated that GC/memory pathway of B cell differentiation is driven by specialized helper T cell (TH) subsets. These TH will be isolated by cell sorting and cellular cloning and their properties and mechanisms of action will be studied in vivo upon adoptive transfer into B cell-reconstituted scid mice immunized with hapten- carrier conjugates. The development of germinal centers (GC) in the spleen will be monitored by immunohistochemical techniques and the affinities of hapten-specific serum antibodies will be determined. The somatic hypermutation activity in the GC B cells will be studied by the sequence analysis of the rearranged VDJ segments that encode the H chains of hapten-specific Ab. Second, it is proposed that the GC/memory response may selectively stimulated with complexes of antigen (Ag) with antibody (Ab). This hypothesis will be tested using well-defined Ab of known isotype and affinity and the mechanism of the Ag/Ab complex activity in conjunction with the help provided by specific TH subsets and clones will be studied. Thirdly, it is proposed to determine whether the memory B cells home to bone marrow which appears to be a major site of the anamnestic Ab response and whether the bone marrow environment contribute to an additional molecular and functional maturation of the anamnestic antibody repertoire. The proposed studies will elucidate important mechanisms of immunological memory, provide tools for manipulation of the adaptive immune response and suggest novel strategies for vaccination.